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Thursday, 25 June 2020

Anti Epileptic Drugs

Seizures

  • Focal -only a portion of brain or hemisphere
      • Simple - single limb or muscle group,no loss of consciousness
      • Complex  - chewing movements, diarrhea, urination ,with loss of consciousness
  • Generalized - immediate loss of consciousness
      • Absence - rapid eye blinking for 3-5 seconds
      • Myoclonic - short episode of muscle contraction
      • Tonic - increased tone in extensor muscles for 60 seconds
      • Clonic - muscle contraction with more altered consciousness
      • Tonic clonic - continuous contraction and rapid movement
      • Atonic - sudden loss of muscle tone

Epilepsy

Predisposition to recurrent unprovoked seizures

Mechanisms

  • Abnormal neuronal circuits
  • Channellopathis
  • Increased excitation
      • increased Na influx
      • increased Ca influx
      • decreased K efflux
  • Decreased inhibition
      • reduced GABA activity
Treatment Methods
  1. Ion channel block
      • Na
      • Ca
  2. Reduce Glutamate activity
  3. Increase GABA activity
      • increase post synaptic action of GABA
      • decrease GABA transaminases
      • decrease GABA re uptake in to glial cells

1. PHENITOIN

  • Use dependent Na channel blocker
  • only inactivated Na channels will be blocked(so only repetitively discharging & high frequent channels)
  • slowly absorbed (85%) metabolized by the liver
  • half life 12-36 h
  • CYP450 inducer
  • metabolism is increased by - Phenobarbitone, Valproate, Isoniazid
  • ADE
    • Cosmetic - gum hyperplasia , acne , hirsutism , focal coarsening
    • cognitive impairment
    • osteomalacia
    • megaloblastic anaemia
    • teratogenic
    • Toxicity - drowsiness , diplopia , dysarthria
  • Uses
    • Status epilepticus
    • Trigeminal neuralgia
    • Myotonic dystrophy


2.CARBAMEZAPINE

  • Na channel blocker
  • CYP450 inducer
  • no loading doses as it ca cause toxicity
  • ADE
    • rash
    • drowsiness, imbalance, diplopia, ataxia
    • rarely - agranulocytosis, SIADH, hyponatreamia
    • folic acid defeciency & osteomalacia
  • Uses
    • partial seizures
    • neuropathic pain
    • maniac depressive illness
  • Ox carbamezapine
    • similar pro drug with less enzyme induction

3.LAMOTRIGINE

  • Action
    • Na channel block
    • Ca channel block
    • reduce Glutamate release
  • metabolized by liver.
    • increased by - phenytoin, carbomezapine, phenobarbitone
    • reduced by - valproate
  • Uses
    • partial/generalized seizures
    • absence seizures

4.SODIUM VALPROATE

  • Action
    • Na channel block
    • T type Ca channel blok
    • GABA potentiation
    • inhibit GABA transaminases
  • CYP450 Inducer
  • ADE
    • dyspepsia
    • tremor
    • weight gain
    • impaired glucose tolerance
    • hepatotoxic
    • teratogenic - neural tube defects
    • hair loss
  • Uses
    • Tonic clonic 
    • Bipolar depressive disorder
    • Absence seizures

5.PHENOBARBITONE

  • Action
    • potentiate GABA receptor activation
  • CYP450 inducer
  • half life 72 - 144 h
  • ADE
    • sedation with therapeutic levels
    • changes in cognition, mood & behaviour
    • megaloblastic changes
    • osteomalacia
    • hypersensitive reaction
    • addiction
    • depress brain stem functions
    • coma, respiratory failure, cardiac arrest

6.CLONAZAPAM

  • Action
    • enhance GABA receptor activation
    • T type Ca channel inhibition
  • ADE
    • sedation
    • tolerance with prolong use

7.VIGABATRIN

  • Action
    • Irreversible inhibition of GABA transaminases
  • ADE
    • tunnel vision - 6 month visual field monitoring

8.GABAPENTIN

  • Action
    • inhibit Glutamate release by blocking high voltage Ca channels
  • No effect on metabolizing enzymes
  • eliminated unchanged in urine
  • half life is 6h so given tds
  • ADE
    • sedation
    • fatigue
    • weightgain
  • Uses 
    • adjunctive therapy for partial seizures

9.TOPIRAMATE

  • Action
    • Na ,Ca channel block
    • GABA potentiation
    • Glutamate receptor block
    • Carbonic anhydrase inhibitor
  • ADE
    • sedation
    • fatigue
    • renal calculi
    • weight loss
    • increased intra occular pressure

10.LEVATIRACETAM

  • Action
    • inhibit Glutamate release
  • renal elimination- unchanged
  • Uses
    • migraine prevention
    • partial seizures

11.ETHOSUXIMIDE

  • Action
    • T type Ca channel block
  • Uses
    • absence seizure treatment
  • ADE 
    • dyspepsia
    • ataxic imbalance

Carbamezapine is relatively safe in pregnancy with vit K & folic acid supplementation.

  • valproate - neural tube defects
  • phenytoin - cleft palate
  • phenobarbitone - cardiac malformations



Drugs according to the mechanism of action

  • Ion channel block

      • Na - phenytoin, carbemezapine, lamotrigine, Na valproate, topiramate 
      • Ca - lamotrigiine, Na valproate, topiramate, ethosuximide

  • Reduce Glutamate activity - lamotrigine, gabapentine,                                                                topiramate, livetiracetam

  • Increase GABA activity

      • increase post synaptic action of GABA -phenobarbitone, clonezapam,  Na valproate, topiramate, 
      • decrease GABA transaminases - Vigabatrin, Na valproate
      • decrease GABA re uptake in to glial cells - Tigabine






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